Pathologically altered alpha-synuclein fibrillizes and forms Lewy bodies (LBs) and Lewy neurites in Parkinson's disease (PD) and related disorders referred to as synucleinopathies because alpha-synuclein inclusions are the predominant brain lesions in these diseases. However, similar lesions are abundant in a common subtype of sporadic Alzheimer's disease (AD) known as the LB variant of AD (LBVAD), as well as in familial AD and Down's syndrome, while LBs and Lewy neurites have been reported in some tauopathies such as progressive supranuclear palsy (PSP) and Guam amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Moreover, while glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA) are composed of fibrillized alpha-synuclein, aggregated tau predominates in a subset of GCIs. Thus, fibrillary deposits of alpha-synuclein, Abeta and tau co-occur in neurodegenerative diseases, and some cells harbor both alpha-synuclein and tau inclusions. Since we showed alpha-synuclein promotes tau fibrillization into homopolymeric filaments, we hypothesize that alpha-synuclein interacts with amyloidogenic tau and Abeta in synucleinopathies to induce their oligomerization and/or fibrillization. Indeed, oligomers of tau and Abeta could contribute to neurodegeneration in synucleinopathies before coalescing into morphologically detectable fibrillar inclusions. Thus, we now propose to test the hypothesis that pathological alpha-synuclein interacts with tau and Abeta to promote their oligomerization, fibrillization and accumulation in synucleinopathy brains while heat shock proteins may mitigate this. The elucidation of mechanisms underlying neurodegenerative brain amyloidoses involving alpha-synuclein, tau and Abeta is essential for the design of more effective therapeutic interventions for synucleinopathies.